American Society of Clinical Oncology Clinical Practice
Guideline: Update on Adjuvant Endocrine Therapy for
Women With Hormone Receptor–Positive Breast Cancer
Harold J. Burstein, Ann Alexis Prestrud, Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz,
Nancy E. Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis, Jennifer Malin,
Eleftherios P. Mamounas, Diana Rowden, Alexander J. Solky, MaryFran R. Sowers, Vered Stearns,
Eric P. Winer, Mark R. Somerfield, and Jennifer J. Griggs
From the Dana-Farber Cancer Institute,
Boston, MA; American Society of Clinical Oncology, Alexandria, VA; Breast
Cancer Coalition of Rochester; Interlakes Oncology and Hematology, Rochester; Memorial Sloan-Kettering Cancer
Center, New York, NY; M. D. Anderson
Cancer Center, Houston; Susan G.
Komen for the Cure, Dallas, TX; University of Pittsburgh Cancer Institute, Pittsburgh, PA; British Columbia Cancer
Agency, Vancouver, British Columbia,
Canada; Greater Los Angeles Veterans
Affairs Healthcare System, Los Angeles, CA; Aultman Health Foundation,
Canton, OH; Johns Hopkins School of
Medicine, Baltimore, MD; and University of Michigan and University of Michigan Comprehensive Cancer Center,
Ann Arbor, MI.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd,
Suite 800, Alexandria, VA 22314;
e-mail: guidelines@asco.org.
© 2010 by American Society of Clinical
Oncology
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Purpose
To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for
postmenopausal women with hormone receptor–positive breast cancer.
Methods
A literature search identified relevant randomized trials. Databases searched included MEDLINE,
PREMEDLINE, and the Cochrane Collaboration Library, along with those of the American Society
of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium (SABCS). The primary
outcomes of interest were disease-free survival, overall survival, and time to contralateral breast
cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed
the literature, considering 12 major trials, and developed updated recommendations.
Results
An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial
endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI
after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5
years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as
sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs
differ in their adverse effect profiles, and these differences may inform treatment preferences.
Conclusion
The Update Committee recommends that postmenopausal women with hormone receptor–
positive breast cancer consider incorporating an AI therapy at some point during adjuvant
treatment, either as upfront therapy or as sequential treatment after tamoxifen. The optimal timing
and duration of endocrine treatment remain unresolved. The Update Committee supports careful
consideration of adverse effect profiles and patient preferences in deciding whether and when to
incorporate AI therapy.
INTRODUCTION
Adjuvant endocrine therapy reduces the risk of
breast cancer recurrence and improves overall
survival among women with hormone receptor–
positive breast cancer. Tamoxifen is the historic
standard adjuvant endocrine therapy.1 On the basis
of data for the role of aromatase inhibitors (AIs) as
treatment for postmenopausal patients with metastatic breast cancer, multiple adjuvant trials comparing AI-based therapy against tamoxifen were
initiated and have been reported.
The first technology assessment for the use of
AIs in the adjuvant setting for women with hormone
receptor–positive breast cancer was published by the
American Society of Clinical Oncology (ASCO) in
20022 following release of early findings from the
Arimidex, Tamoxifen, Alone or in Combination
(ATAC) trial. The technology assessment was updated in 20033 and 20044 on the basis of data from
trials of primary, sequential, and extended adjuvant
treatment with AIs. Since then, additional reports
from large-scale trials of adjuvant endocrine therapy
have been published. Collectively, these developments warranted a timely update and systematic
literature review of data on the efficacy of adjuvant endocrine therapy for women with hormone
receptor–positive breast cancer. Accordingly, the
ASCO Guideline Update Panel (Appendix Table
A1) reconvened to develop an update.
ASCO’s practice guidelines reflect expert consensus based on clinical evidence and literature
© 2010 by American Society of Clinical Oncology
1
available at the time they are written and are intended to assist physicians in clinical decision making and to identify questions and settings
for further research. Because of the rapid flow of scientific information
in oncology, new evidence may have emerged since the guideline was
submitted for publication. Guidelines and assessments are not continually updated and may not reflect the most recent evidence. Guidelines address only the topics specifically identified in the guideline and
are not applicable to interventions, disease, or stages of disease not
specifically identified. Guidelines cannot account for individual variation among patients and cannot be considered inclusive of all proper
methods of care or exclusive of other treatments. It is the responsibility
of the treating physician or other health care provider, relying on
independent experience and knowledge of the patient, to determine
the best course of treatment for the patient. Accordingly, adherence to
any guideline is voluntary, with the ultimate determination regarding
its application to be made by the physician in light of each patient’s
individual circumstances. ASCO guidelines describe the use of procedures and therapies in clinical practice and cannot be assumed to
apply to the use of these interventions in the context of clinical trials.
ASCO assumes no responsibility for any injury or damage to persons
or property arising out of or related to any use of ASCO’s guidelines, or
for any errors or omissions.
UPDATE METHODOLOGY
Guideline Questions
In 2004, the ASCO technology assessment on the use of AIs in the
adjuvant setting identified multiple unanswered questions regarding
optimal endocrine treatment for postmenopausal women.4 New data
on these remaining questions formed the foundation for this guideline
update. The Update Committee focused on the optimal adjuvant
endocrine strategy with use of either tamoxifen, AIs, or both in sequence; the appropriate duration of AI therapy; the long-term adverse
effects of AI therapy; identification of subpopulations who might
derive selective benefit from either AI- or tamoxifen-based treatments; efficacy of AIs among premenopausal women; and similarities
or differences among commercially available third-generation AIs.
Literature Review and Analysis
Literature search strategy. The literature search for this update
was facilitated by the systematic review completed by Cancer Care
Ontario (CCO) that reviewed available literature through May
2007.5 ASCO guidelines staff conducted additional searches of the
MEDLINE, PREMEDLINE, and Cochrane Collaboration Library
electronic databases for published articles from May 2007 through
February 2009 (list of MEDLINE search terms, Appendix). In addition, electronic databases for presentations, posters, and abstracts
presented at the San Antonio Breast Cancer Symposium (SABCS) and
ASCO Annual Meetings in 2007 and 2008 were searched. Additional
sources were identified by hand-searching bibliographies of relevant
articles. Search terms included all the agents under consideration
(“tamoxifen,” “anastrozole,” “exemestane,” “letrozole,” and “aromatase inhibitors”) along with identified brand names (including
European and North American versions). These terms were combined with the disease terminology “breast neoplasms,” “carcinoma,”
“adenocarcinoma,” and “tumor.” The search was limited to phase III
randomized, controlled trials; meta-analyses; systematic reviews; and
2
© 2010 by American Society of Clinical Oncology
existing practice guidelines. Other trial designs, including phase I or II
trials and either prospective or retrospective cohort studies, were excluded. English-language studies available in full text and published in
peer-reviewed journals were included. Following the Update Committee meeting, ASCO staff searched the programs for ASCO’s 2009
Annual Meeting and the 2009 SABCS meeting to include updated data
from the trials described therein.
Inclusion and exclusion criteria. Articles identified for inclusion
in this systematic review met the following criteria: (1) the intervention was for the adjuvant therapy of breast cancer, (2) participants
were randomly assigned to any of the treatments described previously,
and (3) reports included at least one of the following primary outcomes of interest: overall survival, disease-free survival, or breast
cancer-specific survival. Three different treatment strategies were
identified on the basis of the timing of AI therapy: initial endocrine
therapy (hereafter referred to as a primary adjuvant strategy), sequential therapy with treatment divergence if the patient was disease-free
following 1 to 4 years of initial treatment with adjuvant endocrine
agents (most often tamoxifen), or extended therapy with random
assignment if the patient was disease-free following 5 years of treatment with adjuvant tamoxifen. Trials that used earlier generations of
AIs, included neoadjuvant therapy, reported laboratory but not primary disease-related outcomes of interest, or were not randomized
were excluded. Trials that treated patients with metastatic breast cancer were also excluded.
Data extraction. Reports and publications that met inclusion
criteria were identified in a first round of review by members of the
ASCO staff. The Update Committee co-chairs subsequently reviewed
the list of articles, and staff obtained full-text copies of papers that
satisfied the inclusion criteria. ASCO staff completed full-text review
of these articles, including assessment of inclusion and exclusion criteria. Articles that provisionally met inclusion criteria underwent data
extraction for patient characteristics, study design and quality, interventions, outcomes, and adverse events. Evidence summary tables
were reviewed for accuracy and completeness by an ASCO staff member who was not involved in their original preparation.
Study quality and limitations of the literature. Twelve prospective, randomized clinical trials originally identified by the co-chairs
were the focus of this systematic review. These same trials were identified in the CCO systematic review, as well as in a systematic review
completed by the National Institute for Health Research (NIHR) in
the United Kingdom.6 No other relevant randomized studies were
identified during the literature search and review. Four meta-analyses
identified from the search were also considered. The included trials
had varying methodologic quality.
Several important limitations of the existing literature were identified. Of particular note is the timing of random assignment (Fig 1).
Most of the sequential trials and all the extended trials randomly
assigned women who were free of recurrence through multiple
years of tamoxifen therapy, effectively excluding women with early
recurrence. For this reason, the patient populations in the sequential
and extended trials may differ importantly from one another and from
those patients in the primary therapy studies. Another limitation is the
relatively short follow-up time. Postmenopausal breast cancer is a
disease with a long natural history, and disease recurrence decades
after diagnosis is not uncommon. The longest available median
follow-up in the trials included here is slightly more than 8 years;
most studies have considerably shorter follow-up. For the majority
Trial
-5
-4
-3
-2
Time Since Random Assignment
-1
0
1
2
3
4
5
Primary Adjuvant
ATAC118
60-month strategy; median follow-up 100 mos
Postmenopausal, HR (+)
TAM
ANA
TAM + ANA
BIG 1-9839
60-month strategy
Median follow-up 76 mos (monotx), 71 mos (switching)
Postmenopausal, HR (+)
LET
TAM
LET (2 yrs), TAM (3 yrs)
TAM (2 yrs), LET (3 yrs)
TAM + GOS
ANA + GOS
TAM + GOS + ZOL
ANA + GOS + ZOL
ABCSG-1222
36 month strategy
Median follow-up 47.8 mos
Premenopausal, ER and/ or PR (+)
Sequencing
ABCSG-864
Primary random assignment
60 month strategy; median follow-up 72 mos
Postmenopausal, ER(+)/PR(+), no chemo
ITA119
Randomly assigned to 2-3 yrs tx (5 yrs total)
Median follow-up 64 mos
Postmenopausal, ER(+), Node (+)
TEAM32
Primary random assignment
60 month strategy; Follow-up 61 mos
Postmenopausal, ER and/or PR (+)
IES120
Randomly assigned to 2-3 yrs tx (5 yrs total)
Median follow-up 55.7 mos
Postmenopausal, ER(+) or unknown
NSAS BC-038
Randomly assigned to 1-4 yrs tx (5 yrs total)
Median follow-up 42 mos
Postmenopausal
ARNO 95121
Randomly assigned to 3 yrs tx (5 yrs total)
Median follow-up 30.1 mos
Postmenopausal, hormone responsive
TAM
TAM (2 yrs), ANA (3 yrs)
TAM
TAM (2-3 yrs)
ANA
TAM (2½ yrs), EXE (2½ yrs)
EXE
TAM
TAM (2-3 yrs)
EXE
TAM
TAM (1-4 yrs)
ANA
TAM
TAM (2 yrs)
ANA
Extended Adjuvant
MA.17122
5 yrs of TAM, randomly assigned to 60 mos of tx
Median follow-up 64 mos
Postmenopausal, HR(+)
ABCSG-6a123
5 yrs TAM, randomly assigned to 36 mos of tx
Median follow-up 62.3 mos
Postmenopausal, endocrine responsive
NSABP B-33124
5 yrs of TAM, randomly assigned to 60 mos of tx
Median follow-up 30 mos
Postmenopausal, ER or PR (+)
LET
TAM
Placebo
ANA
TAM
Placebo
EXE
TAM
Placebo
Fig 1. Schema of included trials. ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); mos, months; HR (⫹), hormone receptor–positive; TAM, tamoxifen; ANA,
anastrozole; BIG, Breast International Group; FU, follow-up; monotx, monotherapy; LET, letrozole; yrs, years; ABCSG, Austrian Breast and Colorectal Cancer Study
Group; ER (⫹), estrogen receptor–positive; PR (⫹), progesterone receptor–positive; GOS, goserelin; ZOL, zoledronic acid; ABCSG, Austrian Breast and Colorectal
Cancer Study Group; Chemo, chemotherapy; ITA, Italian Tamoxifen Anastrozole (trial); tx, therapy; TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE,
exemestane; IES, Intergroup Exemestane Study; Unk, unknown; N-SAS, National Surgical Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National
Surgical Adjuvant Breast and Bowel Project.
© 2010 by American Society of Clinical Oncology
3
of the efficacy outcomes across all studies, the median time to event
has yet to be reached. The relatively modest number of events may
also limit study conclusions.
The randomized trials for adjuvant AI therapy are large; in fact,
these are some of the largest prospective cancer treatment trials ever
conducted. Nonetheless, the number of actual events was modest
because of the generally favorable prognosis among eligible patients.
Multiple subset analyses have been performed within these trials.
Owing to the vagaries of data collection and patient participation, as
well as the distribution of clinical subsets, subgroup evaluations are
hindered by relatively small sample sizes. Small sample size is also a
limitation in analyzing available quality-of-life and other substudy
data. These substudies frequently included fewer than 10% of patients participating in the master trial. Finally, comparisons between trials are hindered because of different definitions of study
end points such as disease-free survival.7 Studies were generally,
but not entirely, consistent in their working definitions of
treatment- and breast cancer–related events, and they varied considerably in how investigators tabulated and reported efficacy and
adverse effects. Specific instances of variation in efficacy definitions
include classification of in situ carcinoma, non– breast cancers, and
deaths from noncancer causes.
Consensus Development Based on Evidence
The Update Committee met twice, first in San Antonio in December 2008 and again at ASCO Headquarters in April 2009. The
Update Committee was charged with updating the clinical questions, reviewing evidence collected from the systematic review, and
drafting the new recommendations (Table 1). Additional work on
the guideline was primarily completed by the co-chairs and ASCO
staff. The draft guideline document was developed by the co-chairs
and ASCO staff and reviewed by the entire Update Committee. Per
standard ASCO practice, the guideline was submitted to the Journal of Clinical Oncology for peer review. The content of the guideline was reviewed and approved by both the ASCO Clinical
Practice Guideline Committee and the Board of Directors before publication.
Guideline and Conflicts of Interest
The Update Committee was assembled in accordance with ASCO’s
Conflict of Interest Management Procedures for Clinical Practice
Guidelines (“Procedures,” summarized at www.asco.org/guidelinescoi).
Members completed ASCO’s disclosure form, which requires disclosure of financial and other interests relevant to the subject matter of
the guideline, including relationships with commercial entities
that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline.
Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the
majority of the members of the Update Committee did not disclose
any such relationships.
Table 1. Summary of 2010 Recommendations
Clinical Question
Recommendation
1a. What adjuvant
endocrine treatments
should be offered to
postmenopausal
women with hormone
receptor–positive
breast cancer?
1b. What is the appropriate
duration of adjuvant
endocrine therapy?
Postmenopausal women should consider
taking an AI during the course of adjuvant
treatment to lower recurrence risk, either
as primary therapy or after 2 to 3 years of
tamoxifen. Duration of AI therapy should
not exceed 5 years.
1c. If tamoxifen is
administered first, how
long should it be
continued before the
switch to an AI?
2. Are there specific
patient populations that
derive differing degrees
of benefit from an AI in
comparison to
tamoxifen?
3. What are the toxicities
and risks of adjuvant
endocrine therapy?
4. Are AIs effective
adjuvant therapy for
women who are
premenopausal at the
time of diagnosis?
5. Can the thirdgeneration AIs be used
interchangeably?
Therapy with an AI should not extend
beyond 5 years in either the primary or
extended adjuvant settings outside the
clinical trials setting. In the sequential
setting, patients should receive an AI after
2 or 3 years of tamoxifen for a total of 5
years of adjuvant endocrine therapy.
Patients initially treated with an AI but
who discontinue treatment before 5 years
of therapy should consider incorporating
tamoxifen for a total of 5 years of
adjuvant endocrine therapy.
Patients who initially receive tamoxifen as
adjuvant therapy may be offered an AI
after 2 to 3 years (sequential) or after 5
years (extended) of therapy. The best
time to switch from an AI to tamoxifen (or
the converse) is not known. Switching at
2 to 3 years is recommended, but
switching at 5 years is also supported by
available data.
A specific marker or clinical subset that
predicts which adjuvant treatment
strategy (tamoxifen alone, AI alone, or AI
and tamoxifen-based) is best has not
been identified. Among men with breast
cancer, tamoxifen remains the standard
adjuvant endocrine treatment. The
CYP2D6 genotype is not recommended to
select adjuvant endocrine therapy. Caution
with concurrent use of CYP2D6 inhibitors
(such as bupropion, paroxetine, or
fluoxetine) and tamoxifen is
recommended because of drug-drug
interactions.
Clinicians should consider adverse effect
profiles, patient preferences, and preexisting conditions when discussing
adjuvant endocrine strategies. Adverse
effect profiles should be discussed with
patients when presenting available
treatment options. Clinicians may
recommend that patients change
treatments if adverse effects are
intolerable or patients are persistently
noncompliant with therapy.
Women who are pre- or perimenopausal at
diagnosis should be treated with 5 years
of tamoxifen.
Meaningful clinical differences between the
commercially available third-generation AIs
have not been demonstrated to date. The
Update Committee believes that
postmenopausal patients intolerant of one
AI may be advised to consider tamoxifen
or a different AI.
Abbreviation: AI, aromatase inhibitor.
RESULTS
Summary of the Literature Review Results
The preliminary literature search identified 442 published articles and 42 presentations, posters, or abstracts presented at either the
4
© 2010 by American Society of Clinical Oncology
SABCS or the ASCO Annual Meeting (Fig 1). Of these, 52 provisionally met the inclusion criteria and were obtained for full-text review.
Three were excluded from data extraction for failure to meet inclusion
criteria, yielding 49 reports that underwent data extraction. These 49
reported either findings from one of the 12 trials8-50 or were systematic
reviews or meta-analyses of the same.5,51-55 Thirteen additional articles with primary data reports from key studies published before the
date range searched were retrieved for data to complement extraction.
Five reports available after completion of the initial search, including
four presentations from the 2009 SABCS conference, were also considered; longer follow-up was presented for both the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial and the Intergroup
Exemestane Study (IES).56,57
Twelve randomized trials, including three trials of primary therapy (ATAC, Breast International Group [BIG] 1-98, and Austrian
Breast and Colorectal Cancer Study Group ABCSG-12), seven trials of
sequential therapy (IES, BIG 1-98, ABCSG-8, Arimidex-Nolvadex
[ARNO] 95, Italian Tamoxifen Anastrozole [ITA], National Surgical
Adjuvant Study [N-SAS] BC-03, and TEAM), and three trials of extended adjuvant therapy (MA.17, National Surgical Adjuvant Breast
and Bowel Project NSABP B-33, and ABCSG-6a), investigated incorporation of an AI as adjuvant therapy. All of these compared outcomes
against the historical standard of 5 years of tamoxifen therapy, with the
exception of the TEAM trial, which compared a tamoxifen sequence
followed by an AI against an AI alone. Four meta-analyses51-53,55 and
two systematic reviews5,54 were identified.
GUIDELINE RECOMMENDATIONS
Clinical question 1a. What adjuvant endocrine treatments should
be offered to postmenopausal women with hormone receptor–positive
breast cancer?
Recommendation 1a. The Update Committee recommends, on
the basis of data from randomized, controlled trials, that most postmenopausal women consider taking an AI during the course of adjuvant treatment to lower recurrence risk, either as primary therapy or
after 2 to 3 years of tamoxifen—strategies that yield equivalent outcomes in prospective studies. Duration of AI therapy should not
exceed 5 years.
Literature update and discussion 1a. At the time of the last update, data were available from four randomized trials that evaluated
adjuvant treatment incorporating AI therapy against 5 years of tamoxifen. On the basis of the available data, the 2004 Update Committee
noted that “adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer should include an AI to lower
the risk of tumor recurrence. Neither the optimal timing nor duration
of AI therapy is established.”4
Since then, reports of related studies have emerged, and data
from the original trials have matured. In comparison to 5 years of
Table 2. Disease-Free Survival
Trial
Primary
ATAC21
BIG 1-9842
ABCSG-1223
Sequential
BIG 1-9842
ABCSG-830
ITA10
TEAM57
IES14
N-SAS BC-039
ARNO 9534
Extended
MA.1726
ABCSG-6a31
NSABP B-3337
Arm
Median
Follow-Up
(months
ANA v TAM ITT
LET v TAM ITT
ANA v TAM
100
76
47.8
TAM/LET v LET
LET/TAM v LET
TAM/ANA v TAM ITT
ITT
TAM/EXE v EXE ITT
ITT
71
71
72
64
61
55.7
42
30.1
ITTg
64
62.3
30
Range
(months)
0-126
12-93
0-89.7
3.2-60
⬍ 12 to ⱖ 84
16-95
No. of Patients
Observed
Disease-Free Survival
Events
AI
Comparator
AI
Comparator
No.
%
No.
%
HR
95% CI
P
3,125
2,463
903
3,116
2,459
900
817
509
72
26.1
20.7
8.0
887
565
65
28.5
23.0
7.2
0.90
0.88
1.10
0.82 to 0.99
0.78 to 0.99a
0.78 to 1.53
1,548
1,540
1,865
223
4,868
2,352
347
489
1,546
1,546
1,849
225
4,898
2,372
349
490
259
236
227
39
714
354
26
38
16.7
15.3
12.2
17.5
16.0
16.0
14.1
28
7.5
7.8
248
248
261
63
712
455
37
56
10.6
11.4
1.05
0.96
0.85
0.57
0.97
0.76
0.69
0.66
0.84 to 1.32b
0.76 to 1.21b
0.71 to 1.01c,d
0.38 to 0.85e
0.88 to 1.08
0.66 to 0.88
0.42 to 1.14
0.44 to 1.00
NR
NR
.067
.005
.604
⬍ .001
.14f
.049
2,583
386
783
2,587
466
779
164
30
37
6.3
7.8
4.7
235
57
52
9.1
12.2
6.7
0.68
0.62
0.68
0.55 to 0.83
0.40 to 0.96h
⬍ .001
.031
.07
.025
.03
.59
NOTE. Percent calculated as number of events divided by number of patients observed.
Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; ITT, intent
to treat; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; NR, not reported; ITA, Italian Tamoxifen
Anastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical
Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.
a
Analysis includes only patients from monotherapy arms; crossovers not censored.
b
99% CIs used to account for multiple comparisons.
c
Relapse-free survival includes local and distant recurrence, contralateral breast cancer, and death without recurrence.
d
Patients who crossed over were censored at time of crossover.
e
Event-free survival includes locoregional or distant recurrence, second primary (including contralateral breast cancer), and deaths without recurrence.
f
Two different P values reported (P ⫽ .06 in abstract, P ⫽ .14 on poster).
g
Seventeen patients omitted from ITT analysis.
h
Recurrence-free survival.
© 2010 by American Society of Clinical Oncology
5
Table 3. Contralateral Breast Cancer
Trial
Primary
ATAC21
BIG 1-986
TEAM33
Sequential
ABCSG-830
IES14
ARNO 9534
Extended
MA.1729
ABCSG-6a31
Arm
Median
Follow-Up
(months
ANA v TAM ITT
LET v TAM
EXE v TAM ITTⴱ
100
68
33†
TAM/ANA v TAM ITT
ITT
72
55.7
30.1
64
62.3
Range
(months)
0-89.7
⬍ 12 to ⱖ 84
No. of Patients
Observed
Contralateral Breast Cancer
Events
AI
Comparator
AI
Comparator
No.
%
No.
%
HR
95% CI
P
3,125
4,003
4,898
3,116
4,007
4,868
61
16
21
1.9
0.4
0.4
87
27
17
2.8
0.7
0.3
0.68
NR
NR
0.49 to 0.94
NR
NR
.02
NR
NR
1,865
2,352
489
1,849
2,372
490
19
18
7
1.0
0.76
1.4
29
35
5
1.6
1.5
1
0.64
0.57
NR
0.36 to 1.13
0.33 to 0.98
NR
NR
.04
NR
2,583
386
2,587
466
30
6
1.16
1.6
49
11
1.89
2.4
0.61
0.67
0.39 to 0.97
0.25 to 1.80‡
.033
.422
NOTE. Percent calculated as number of events divided by number of patients observed.
Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ITT, intent to treat; BIG, Breast International
Group; LET, letrozole; TAM, tamoxifen; NR, not reported; TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; ABCSG, Austrian Breast
and Colorectal Cancer Study Group; ANA, anastrozole; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial).
ⴱ
Data for contralateral risk in the TEAM trial have been reported for comparison of initial therapy of TAM v EXE but not for TAM/EXE v EXE at this time.
†Follow-up for all TEAM patients is 33 months (data beyond that censored).
‡Risk of contralateral breast cancer.
tamoxifen alone, use of an AI in either primary, sequential, or extended treatment has been found to improve disease-free survival
(Table 2), reducing the risk of breast cancer events including distant
recurrence, locoregional recurrence, and contralateral breast cancer
(Table 3). In absolute terms, the reduction in risk of recurrence associated with AI-based therapy compared with tamoxifen is modest,
typically amounting to ⬍ 5% through multiple years of follow-up
(Table 2). At present, tamoxifen and AI-based therapy are equivalent
in terms of overall survival when used as either a primary or extended
treatment strategy (Table 4). Two of the six trials of sequential treatment strategies yielded statistically significant improvements in overall survival compared with tamoxifen alone, although the absolute
difference in overall survival is modest (Table 4).
Breast cancer events such as locoregional recurrence, contralateral breast cancer, and early distant metastatic recurrence are
clinically important to patients. For this reason, the Update Committee recommended consideration of AI therapy at some time during the
course of adjuvant endocrine therapy, even though few trials, and
none of the primary studies, demonstrated statistically significant
differences in overall survival.
Sequential therapy. Two trials directly compared primary
monotherapy with sequential therapy as an initial, 5-year adjuvant
endocrine regimen. BIG 1-98 compared primary tamoxifen or AI
monotherapy against sequences of tamoxifen followed by an AI or an
AI followed by tamoxifen.40 TEAM compared a sequential treatment
of tamoxifen followed by an AI against an AI alone.57,58 Neither study
demonstrated clinically or statistically significant differences between
patients who received an AI alone, tamoxifen sequenced with an AI or,
in the case of BIG 1-98, an AI sequenced with tamoxifen, with respect
to disease-free or overall survival. In BIG 1-98, however, each AI-based
therapy was superior to tamoxifen monotherapy with respect to
disease-free survival (Table 2).40 These data support the recommendation to incorporate AI therapy at some point during the first 5 years
6
© 2010 by American Society of Clinical Oncology
of adjuvant endocrine therapy, either as primary therapy or in sequence with tamoxifen.
Clinical question 1b. What is the appropriate duration of adjuvant endocrine therapy?
Recommendation 1b. Therapy with an AI should not extend
beyond 5 years in either the primary or extended adjuvant settings,
outside of clinical trials. In the sequential setting, the Update Committee recommends, on the basis of available evidence from randomized,
controlled trials, that patients receive an AI after 2 or 3 years of
tamoxifen for a total of 5 years of adjuvant endocrine therapy. The
Update Committee recommends that patients who are initially
treated with an AI but discontinue treatment before 5 years of therapy
consider taking tamoxifen for a total of 5 years of adjuvant endocrine therapy.
Literature update and discussion 1b. Importantly, no trials directly compared sequential or extended adjuvant strategies against
one another or primary against extended strategies. The historical
standard duration of tamoxifen therapy is 5 years,59 and 5 years of
tamoxifen is the standard comparator for all adjuvant trials of AIs. The
trials of primary AI treatment strategies administered 5 years of either
tamoxifen or AI therapy. Trials of sequential therapy compared a
sequence of tamoxifen and/or AI therapy for a total 5 years of treatment against 5 years of tamoxifen except for the TEAM trial. That
study evaluated a tamoxifen/exemestane sequence compared with
exemestane monotherapy.57 The three trials of extended adjuvant
therapy evaluated two different durations of AI treatment after 5 years
of tamoxifen: both NSABP B-3337 and MA.1761 compared 5 years of
treatment with placebo while ABCSG-6a62 randomly assigned patients to 3 years of therapy (Fig 1). It is not known whether these
differences in duration of therapy are clinically significant, and optimal duration of therapy in the extended setting is unclear at this time.
Safety and efficacy data from the primary trials support up to 5 years of
Table 4. Overall Survival
Trial
Primary
ATAC21
BIG 1-9842
ABCSG-1223
Sequential
ABCSG-830
BIG 1-9842
ITA10
TEAM57
IES14
N-SAS BC-039
ARNO 9534
Extended
MA.1726
ABCSG-6a31
NSABP B-3337
Arm
ANA v TAM ITT
LET v TAM ITT
ANA v TAM
TAM/ANA v TAM ITT
TAM/LET v LET
LET/TAM v LET
ITT
TAM/EXE v EXE ITT
ITT
ITT§
Median
Follow-Up
(months
No. of Patients
Observed
Range
(months
Overall Survival Deaths
AI
Comparator
AI
Comparator
No.
%
No.
%
HR
95% CI
P
100
76
47.8
3,125
2,463
903
3,116
2,459
900
629
303
27
20.1
12.3
3.0
624
343
15
20.0
14.0
1.7
1.00
0.81
1.8
0.89 to 1.12
0.69 to 0.94ⴱ
0.95 to 3.38
.99
.08
.70
72
71
71
64
61
1,865
1,548
1,540
223
4,868
1,849
1,546
1,546
225
4,898
165
9.0
137
8.9
137
8.9
21
9.3
NR (90.5%
survival)
261
11.0
NR
28
5.7
0.78
1.13
0.90
0.56
1.00
0.62 to 0.98†
0.83 to 1.53‡
0.65 to 1.24‡
0.28 to 1.15
0.89 to 1.14
.032
NR
NR
.1
.999
0.85
NR
0.53
0.71 to 1.02
.08
.59
.045
155
55
13
0.98
0.89
NR
0.78 to 1.22
0.59 to 1.34
55.7
42
30.1
0-89.7
3.2-60
⬍ 12 to ⱖ 84
2,352
347
489
2,372
349
490
138
7.4
154
9.9
123
8.0
12
5.4
NR (90.6%
survival)
222
9.4
NR
15
3.1
64
62.3
30
16-95
2,583
386
783
2,587
466
779
154
40
16
12-93
6.0
10.4
2.0
6.0
11.8
1.7
0.28 to 0.99
.853
.570
NR
NOTE. Percent calculated as number of events divided by number of patients observed.
Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; ITT, intent
to treat; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; NR, not reported; ITA, Italian Tamoxifen
Anastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical
Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.
ⴱ
Analysis includes only patients from monotherapy arms; crossovers not censored.
†Patients who crossed over were censored.
‡99% CIs used to account for multiple comparisons.
§Seventeen patients omitted from ITT analysis.
AI therapy as a primary adjuvant strategy, a duration also used in two
trials of extended therapy after 5 years of tamoxifen.
The treatment regimen for patients in the sequencing trials
spanned 5 years. Thus, no data support clinical benefits for durations
of AIs longer than 2 or 3 years in the context of a sequencing strategy.
In the BIG 1-98 and TEAM trials, patients who received a total of 5
years of sequential therapy that included tamoxifen (2 to 3 years)
followed by an AI (2 to 3 years) had clinical outcomes that were not
significantly different from those for patients who received AI monotherapy.40,57,58 BIG 1-98 also included an arm with an AI followed by
tamoxifen with similar outcomes. These data suggest that shorter
durations of AI treatment might be as effective as longer durations in
women who receive a total of 5 years of endocrine therapy in the
context of a sequencing approach.
Data from randomized, controlled trials demonstrate that
women who receive primary AI therapy should be treated for a total of
5 years; women who initially receive tamoxifen and switch to an AI
should also receive at least five total years of endocrine therapy. No
available data evaluate durations of AI therapy in excess of 5 years
among patients receiving sequential therapy. Women who receive
extended adjuvant therapy should receive 8 to 10 years of total endocrine treatment: 5 years of tamoxifen followed by 3 to 5 years of an AI.
The Update Committee acknowledges that these recommendations yield an unfamiliar pattern of different durations of adjuvant
endocrine treatment based on the treatment strategy used. This is a
function of offering an AI at a different time point in accordance with
each strategy. The recommended limit on AI treatment is 5 years total,
across strategies. Two trials—MA.17R and NSABP B-42—are evaluating whether longer durations of AI therapy improve outcomes, but
results are not yet available.
Clinical question 1c. If tamoxifen is administered first, how long
should it be continued before the switch to an AI?
Recommendation 1c. The Update Committee recommends
that, on the basis of available evidence from randomized, controlled
trials, patients who initially receive tamoxifen as adjuvant therapy may
be offered an AI after 2 to 3 years of therapy (sequential) or after 5 years
of therapy (extended). The time to switch from an AI to tamoxifen (or
the converse) that maximally improves outcomes is not known from
available direct evidence. The Update Committee recommends
switching at 2 to 3 years on the basis of data from sequential trials that
used this strategy. Switching at 5 years is also a strategy supported by
the extended adjuvant randomized trials.
Literature update and discussion 1c. Most, but not all, trials of
sequential therapy switched patients from tamoxifen to an AI after 2 to
3 years of therapy. Some specified an exact crossover point, while
others permitted switching within a broad window. Trials of extended
therapy enrolled patients who already received an average of 5 years of
tamoxifen (Fig 1). Of the sequencing and switching trials, only BIG
1-98,63 TEAM,32 and ABCSG-864 enrolled patients before commencement of adjuvant endocrine therapy. The other sequencing trials and
all the extended trials randomly assigned patients free of recurrence
after multiple years of tamoxifen therapy. Data are lacking to establish
the best duration of tamoxifen therapy before switching to an AI.
© 2010 by American Society of Clinical Oncology
7
Three trials of extended adjuvant therapy using AI treatment for
3 to 5 years after 5 years of tamoxifen demonstrated that extended
therapy can lower the risk of breast cancer recurrence (Table 2 and
Appendix Table A2) and contralateral breast cancer (Table 3) but does
not improve overall survival (Table 4). The Update Committee recommends extended therapy with an AI for postmenopausal patients
who complete 5 years of tamoxifen.
For a newly diagnosed patient or a patient who has been on
tamoxifen for 2 to 5 years, it is not known whether switching from
tamoxifen to an AI earlier or later is more effective for long-term
disease-free survival. Lacking direct comparative data, the Update
Committee recommends considering a switch from tamoxifen to an
AI after 2 or 3 years of tamoxifen therapy. This recommendation is
informed by several observations. First, both ARNO 95 and ABCSG-8,
which transitioned patients from tamoxifen to an AI after 2 or 3 years,
demonstrated survival advantages, as did a meta-analysis of sequential
trials30,34,65 (Table 4). Second, each AI-based arm of BIG 1-98, including those with switching at 2 years, had improved disease-free survival
relative to 5 years of tamoxifen40 (Table 2). These findings suggest that
incorporating an AI into the adjuvant treatment regimen at some
point during the first 5 years of endocrine therapy yields clinical
improvements compared with 5 years of tamoxifen monotherapy,
which justifies considering a switch between years 2 and 3. Data that
compare switching at 2 to 3 or at 5 years are not available. Clinicians
and patients may reasonably opt to consider extended therapy based
on individual considerations.
Clinical question 2. Are there specific patient populations that
derivedifferingdegreesofbenefitfromanAIincomparisontotamoxifen?
Recommendation 2. Direct evidence from randomized trials
does not identify a specific marker or clinical subset that predicted
which adjuvant treatment strategy, tamoxifen or AI monotherapy or
sequential therapy, would maximally improve outcomes for a given
patient. Among men with breast cancer, tamoxifen remains the standard adjuvant endocrine treatment.
The Update Committee recommends against using CYP2D6
genotype to select adjuvant endocrine therapy. The Update Committee encourages caution with concurrent use of CYP2D6 inhibitors
(such as bupropion, paroxetine, fluoxetine; Table 5) and tamoxifen
because of the known drug-drug interactions.
Literature update and discussion 2. A vast historical experience
established prognostic markers for outcomes in early-stage breast
Table 5. Commonly Used CYP2D6 Inhibitors
Strong inhibitors
Bupropion
Fluoxetine
Paroxetine
Quinidine
Moderate inhibitors
Duloxetine
Terbinafine
Weak inhibitors
Amiodarone
Cimetidine
Sertraline
Flockhart DA: http://medicine.iupui.edu/clinpharm/ddis/table.asz.
8
© 2010 by American Society of Clinical Oncology
cancer treated with tamoxifen. Endocrine therapy is effective only
among patients with tumors that express estrogen receptor (ER)
and/or progesterone receptor (PR) hormone receptors.66,67 Tumor
size, nodal status, grade, quantitative levels of hormone receptor expression, HER2 overexpression, markers of proliferation, and the
21-gene recurrence score68 are prognostic factors among patients who
receive endocrine therapy.38 These prognostic markers help to define
relative risk of recurrence in the first 5 to 10 years after diagnosis.
The major trials of adjuvant AI therapy included patients with
hormone receptor–positive tumors, generally irrespective of other
markers or staging. Two trials (ABCSG-8 and ABCSG-12) limited
accrual to patients with lower-grade tumors.22,64 Retrospective subset
analyses (Appendix Table A3) from some trials considered a variety of
prognostic factors among patients receiving tamoxifen or AI-based
therapy. In these retrospective studies, tumor size, nodal status, age,
quantitative ER and PR levels, HER2 expression,45,65 grade, Ki-67,50
and the 21-gene recurrence score69 seem to serve as prognostic factors
for risk of breast cancer recurrence among patients receiving either
tamoxifen or AI therapy (Table 6).
Traditional assumptions about proportionate risk reduction
achieved with adjuvant therapy suggest that differences in clinical
outcome between various treatments are likely to be of greater
absolute magnitude among patients with higher-risk breast cancers. Conversely, among women with lower-risk tumors, differences
in outcomes between AI-based therapies and tamoxifen, or between
primary or sequential use of AIs, are likely to be smaller if present at all.
Emerging data from BIG 1-98 seem to validate these traditional assumptions among postmenopausal women treated with tamoxifen
and/or AIs.38,70 However, the available retrospective subset analyses
are constrained by missing data on some patients, technical limitations in the performance of correlative marker testing, multiple hypothesis testing, varying assays used by different trials, and lack of
prospective, corroborative data.
On the basis of evidence from randomized clinical trials and
consistent with the recommendation, the Update Committee recommended treatment with either upfront use of an AI or sequential
therapy with tamoxifen followed by an AI (or vice versa) for postmenopausal women, irrespective of any specific clinical subset or
prognostic marker studied to date in retrospective analysis.
Male breast cancer. Only women were eligible for the adjuvant
trials of postmenopausal endocrine therapy with AIs. Thus, there is no
evidence to evaluate the efficacy of adjuvant AI therapy in men. Tamoxifen remains the standard adjuvant endocrine therapy for male
breast cancer.71
CYP2D6 genotype. Accumulating data suggest that variability in
tamoxifen metabolism may affect serum levels of the tamoxifen metabolite endoxifen, which may in turn affect the likelihood of cancer
recurrence in patients treated with tamoxifen.71-78 Factors that contribute to this variability include concurrent use of other drugs that
inhibit the CYP2D6 isoenzyme, which converts tamoxifen to endoxifen, and pharmacogenetic variation (polymorphisms) in CYP2D6
alleles. It is not yet known whether variations in CYP2D6 genotype
account for differences in outcomes among patients treated with tamoxifen. Available data on CYP2D6 pharmacogenetics are insufficient to recommend testing as a tool to determine the optimal
adjuvant endocrine strategy.
The Update Committee recognized the accumulating evidence
on drug-drug interactions between tamoxifen and other drugs that
inhibit CYP2D6 (such as bupropion, paroxetine, or fluoxetine; Table
5). The evidence linking such interactions to clinically important
outcomes for breast cancer patients, however, remains limited and
indirect. Alternatives are available for both tamoxifen and CYP2D6
inhibitors. The Update Committee suggests that patients clearly
benefiting from known CYP2D6 inhibitors might consider avoiding tamoxifen because of potential pharmacologic interactions.
Conversely, women who take tamoxifen may prefer to avoid concurrent use of known CYP2D6 inhibitors if suitable treatment alternatives
are available.
Clinical question 3. What are the toxicities and risks of adjuvant
endocrine therapy?
Recommendation 3. The Update Committee recommends that
clinicians consider adverse effect profiles, patient preferences, and
pre-existing conditions when recommending an adjuvant endocrine
strategy for postmenopausal women. Clinicians should discuss adverse effect profiles when presenting available treatment options to
patients. The Update Committee suggests that clinicians consider
recommending that patients change treatment if adverse effects are
intolerable or if patients are persistently noncompliant with therapy.
Literature update and discussion 3. Accumulated experience
with AIs, including data from randomized clinical trials and other
reports in the clinical literature, has increasingly clarified the adverse
effect profile for this drug class. These agents are generally well tolerated but are associated with specific toxicities, including effects on
bone, cardiovascular, and gynecologic health. The Update Committee
did not find evidence that AI therapy is less toxic or better tolerated
than tamoxifen. Both drug classes have distinct adverse effect profiles
that are relevant to individualizing therapy for patients.
Both tamoxifen and AIs are generally well-tolerated therapies.
Substudies from the large, randomized trials show generally wellmaintained and similar quality-of-life scores in women receiving any
of the adjuvant endocrine therapies.19,37,44,49,79-82 The differing adverse effect profiles are functions of differing mechanisms of action.
Tamoxifen is a selective ER modulator with mixed pro- and antiestrogenic activities, while AIs achieve near complete estrogen deprivation in postmenopausal women. The intensity and severity of the
most common adverse effects are mild to moderate for the majority of patients; serious adverse effects are rare. The long-term
adverse effect profiles for tamoxifen-treated patients are established from historical literature.83 Late effects of AI therapy remain
to be fully characterized.
Appendix Tables A4 through A8 include an abbreviated list of the
adverse effects tabulated from the therapies evaluated in the prospective, randomized trials discussed herein. Four main categories of
symptoms are detailed: cardiovascular, musculoskeletal, gynecologic,
and climacteric.
Tamoxifen and AIs have differing effects on cardiovascular
health. Data suggest that AIs are associated with increased cardiovascular disease, possibly including ischemic cardiac disease. Differences
between AIs and tamoxifen in the incidence of serious cardiac disease,
however, are less than 1% at this time (Appendix Tables A4 and
A5).41,52 In comparison to tamoxifen, AI therapy is associated with an
increased risk of both hypercholesterolemia and hypertension. Data
are insufficient to exclude clinically significant differences in cardiovascular disease associated with the AIs. Tamoxifen is associated with
an increased risk of venous thromboembolic events, giving rise to a
1% to 2% greater risk of deep vein thrombosis compared with that of
women taking AIs (Appendix Table A5).52 Data on the relative incidence of stroke with either tamoxifen or an AI are inconclusive.
Longer follow-up is required to better characterize the potential cardiac toxicity of AI therapy.
Tamoxifen and AIs have differing effects on musculoskeletal
health and symptoms. In comparison to tamoxifen, AIs are associated
with greater loss of bone mineral density18 and bone fracture (Appendix Table A6). Discontinuation of AI therapy seems to halt further loss
of bone mineral density.18,22 The incidence of osteoporosis and bone
fractures84 differs by approximately 2% to 4% in trials of primary
adjuvant endocrine therapy comparing tamoxifen with an AI12,20,22;
the risk is increased with AI therapy. Randomized clinical trials suggest
that bisphosphonate therapy can mitigate AI-associated loss of bone
density.22,85-87 The long-term impact of AI treatment on osteoporosis
risk and fracture risk has not been characterized.
With maturation of clinical data and accumulating clinical experience, it is clear that AIs cause a musculoskeletal/arthralgia syndrome.
This syndrome is characterized by bone and joint symptoms, frequently described by patients as pain, stiffness, or achiness that is
symmetric and not associated with other signs of rheumatologic
disorders.47,88-91 The prevalence of this syndrome is unclear, though it
seems widespread; most patients have mild to moderate symptoms.
There are no known interventions of proven value for AI-associated
musculoskeletal symptoms. Discontinuation of AI therapy usually
relieves symptoms within 8 to 10 weeks.
Tamoxifen and AIs have differing effects on gynecologic health.
Adverse events are more common among women receiving tamoxifen. In general, tamoxifen is associated with an increased risk of
uterine cancer, benign endometrial pathology (including bleeding,
polyps, and hyperplasia), hysterectomy, and vaginal discharge (Appendix Table A7). With 5 years of tamoxifen therapy, the risk of
uterine cancer is ⱕ 1%;30 a larger percentage of patients will have
benign endometrial findings or hysterectomy.92,93 Both tamoxifen
and AIs are associated with climacteric symptoms. AIs seem to be less
associated with hot flashes than tamoxifen (Appendix Table A8).
ATAC and MA.17 both reported a lower incidence of vaginal dryness
among patients treated with tamoxifen than among those treated with
AIs.79,82 IES, alternatively, documented similar rates of vaginal dryness
among both tamoxifen- and AI-treated patients,19 and the TEAM
trial57 reported a statistically higher rate of vaginal dryness in patients
who received sequential tamoxifen and exemestane compared with
exemestane alone. Findings were mixed with respect to loss of libido:
MA.17 and IES noted similar rates while AI-treated patients had
higher rates in the ATAC trial.32,80,81 Patients who were given extended adjuvant endocrine therapy with an AI reported more climacteric symptoms than women given placebo therapy.
Evaluation of other adverse effects suggests no major differences
in the incidence or severity of conditions such as skin rashes, eye
symptoms, neurologic function, headache, fatigue, GI symptoms,
psychiatric conditions, or cognitive function between AIs and tamoxifen. No direct data indicate that changing drug agents or classes
alleviates treatment-related symptoms. However, on the basis of limited clinical experience, the Update Committee favored switching
drugs if needed to promote compliance with therapy among patients
whose treatment-related symptoms were intolerable.
Clinical question 4. Are AIs effective adjuvant therapy for
women who are premenopausal at the time of diagnosis?
© 2010 by American Society of Clinical Oncology
9
Recommendation 4. The Update Committee recommends that
women who are pre- or perimenopausal at the time of breast cancer
diagnosis be treated with 5 years of tamoxifen.
Additional considerations. The Update Committee recommends that clinicians use caution in evaluating menopausal status of
patients who are pre- or perimenopausal at diagnosis. Unequivocal
determination of menopausal status may be challenging to prove.
Even among women who have not experienced menses for more than
1 year, laboratory testing is inadequate because patients may recover
ovarian function. This particularly applies to those patients who experience chemotherapy- or tamoxifen-induced amenorrhea.
Literature update and discussion 4. AI therapy has been shown to
be effective only in postmenopausal women. In fact, this class of
drugs is contraindicated in premenopausal women. All of the
adjuvant AI trials, with the exception of ABCSG-12, excluded premenopausal women. All patients accrued to ABCSG-12 were treated
with gonadotropin-releasing hormone agonist therapy to achieve a
postmenopausal state and were randomly assigned to either tamoxifen or anastrozole, each with or without zoledronic acid.23 Eligible
patients had low-grade breast cancer with favorable prognosis, and
none received adjuvant chemotherapy, though 5% did receive
neoadjuvant chemotherapy. Thus, these patients are not necessarily representative of younger women with early-stage breast cancer.
ABCSG-12 demonstrated equivalence with respect to time to recurrence, disease-free survival, and overall survival between tamoxifen
and AI therapy in premenopausal women given ovarian suppression
treatments.23 Thus, there are no data at present to suggest that AIbased therapy is superior to tamoxifen-based therapy in premenopausal women with ovarian suppression treatments. Because of
tamoxifen equivalence with AI therapy in that setting and the occasional failure to achieve menopausal status with ovarian suppression,
the Update Committee strongly recommends tamoxifen as primary
adjuvant endocrine therapy for all pre- or perimenopausal women
and women with treatment-induced amenorrhea.
Some women who were pre- or perimenopausal at the time of
diagnosis may become unequivocally postmenopausal in subsequent
years. For women who become postmenopausal during tamoxifen
treatment after initial diagnosis of premenopausal breast cancer, the
Update Committee suggests considering AIs as either sequential or
extended adjuvant endocrine therapy. Relatively few women in the
studies of sequential or extended therapy met this description. Thus,
the magnitude of benefit for introducing an AI in the subsequent
treatment of such women is not well characterized. Limited retrospective data suggest that such women might benefit from extended adjuvant endocrine therapy with an AI after 5 years of tamoxifen.94
Both chemotherapy and tamoxifen can contribute to amenorrhea. This effect may be transient or permanent, depending on the
patient’s age and therapies received. Multiple reports document late
clinical recovery of ovarian function among women with treatmentinduced amenorrhea, which could render AI therapy ineffective.95,96
Cessation of menses for 1 year is the clinical hallmark of menopause.
However, this clinical definition applies only to women without health
conditions, surgery of the uterus, and those taking medications that
contribute to amenorrhea, such as chemotherapy or tamoxifen, and
thus may not apply to many breast cancer patients.
At present, the role of ovarian suppression in addition to tamoxifen for premenopausal patients is not known. The Suppression of
Ovarian Function Trial (SOFT) is comparing tamoxifen, tamoxifen
10
© 2010 by American Society of Clinical Oncology
plus ovarian suppression, and exemestane plus ovarian suppression,
and it continues to accrue patients. Findings from this trial will further
define best practices for premenopausal patients as well as those patients who experience treatment-induced menopause.
Clinical question 5. Can the third-generation AIs be
used interchangeably?
Recommendation 5. In the absence of direct comparisons, the
Update Committee interprets available data as suggesting that benefits
of AI therapy represent a “class effect.” Meaningful clinical differences
between the commercially available third-generation AIs have not
been demonstrated to date. In the clinical opinion of the Update
Committee (rather than direct evidence from randomized trials),
postmenopausal patients intolerant of one AI but who are still candidates for adjuvant endocrine therapy may be advised to consider
tamoxifen or a different AI.
Literature update and discussion 5. In previous ASCO guidelines
on AIs, available results were limited to reports for the principal use of
a single AI in each of the clinical settings of primary (anastrozole),
sequential (exemestane), or extended (letrozole) adjuvant therapy.
There are still no data from head-to-head comparisons of the AIs.
However, there are data from randomized trials for each of the commercially available third-generation AIs for all of the adjuvant treatment strategies (primary, sequential, extended; Fig 1). The Update
Committee interprets the results with each of these agents in comparison to tamoxifen-based treatment as qualitatively similar with respect
to efficacy and tolerability. Toxicity reports (Appendix Tables A4
through A8) have not suggested obvious clinical advantages of one AI
over another with respect to compliance, constitutional or menopausal symptoms, bone health, cardiovascular disease, or quality of
life. Anecdotal experience suggests that patients may tolerate one AI
better than another, but patterns are neither predictable nor consistent. Two trials—MA.27 and Femara versus Anastrozole Clinical
Evaluation (FACE)—are directly comparing one AI against another as
primary adjuvant therapy. However, data are not yet unavailable from
either trial.
PATIENT COMMUNICATION
The purpose of this section is to address aspects of patient-provider
communication that play a role in decision making about the use of
adjuvant endocrine therapy, the selection of agent, and barriers to
adherence to treatment regimens (taking medication as prescribed)
and persistence with the medication schedule (taking medication for
the full duration prescribed). Separate literature searches and Update
Committee members’ suggestions, rather than the systematic review,
were used to prepare this section.
Patients need to be informed about risk factors for tumor recurrence, the role of residual subclinical (that is, microscopic) disease in
causing recurrence, and the potential benefit of adjuvant endocrine
therapy. Clinicians can base risk estimates in women with hormone
receptor–positive disease on well-established prognostic markers such
as stage, HER2 status, and grade. Emerging molecular diagnostic assays such as the 21-gene recurrence score also seem to serve as prognostic markers in ER-positive, node-negative breast cancer.97,98 Data
summarized in this guideline provide estimates of risk reduction that
can further inform estimates of treatment benefit. Decision tools such
as Adjuvant! Online99 quantify and communicate, in broad terms,
both the risk of cancer recurrence and the benefit of various adjuvant
endocrine treatment strategies based on a patient’s tumor characteristics, comorbidity, age, and receipt of chemotherapy.100 Adjuvant!
Online also includes a feature that estimates the benefit of extended
adjuvant therapy after a 5-year course of adjuvant tamoxifen.
Rates of nonpersistence (early discontinuation of medications)
in women who start taking tamoxifen are as high as 30% at 3 years after
filling a first prescription. For example, a study of 2,816 women taking
tamoxifen between 2001 and 2004 identified a 22% rate of nonpersistence 12 months after starting tamoxifen.101 In another study, among
392 patients enrolled in Medicaid or Pharmacy Assistance programs
in New Jersey between 1990 and 1996, 32% of women discontinued
adjuvant tamoxifen at 2 years and 39% at 3 years.102 Similarly, in a
sample of 961 women 65 years of age or older diagnosed with breast
cancer in 1990 to 1994 in the Cancer Research Network, 24% discontinued tamoxifen after 2 years of treatment, 33% discontinued tamoxifen after 3 years of treatment, and 50% discontinued tamoxifen
before the end of 5 years; discontinuation was not due to recurrent
disease.103 Data from clinical trials104 and claims-based research105
indicate that persistence is no better with AIs. Physicians may underestimate rates of nonadherence and nonpersistence, and patients may
be reluctant to disclose problems with adherence and persistence.
Patient beliefs about the benefits and risks of medications are associated with adherence and persistence; thus, discussing and addressing
such beliefs is warranted.106
Adverse effects are particularly important in precipitating early
discontinuation of therapy. Patients experiencing treatment-related
adverse effects are more likely to discontinue adjuvant endocrine
therapy, particularly during the first years.107,108 In another trial, adverse effects were the most common reason for discontinuation, particularly during the first year. Among those who stopped taking
tamoxifen in the first year, 70% stopped because of adverse effects.103
Patients who experience adverse effects for which they were not
prepared seem to be at particularly high risk for nonpersistence.108
Similarly, musculoskeletal adverse effects of the AIs have been
shown to prompt discontinuation in more than 10% of patients
who start an AI.90 Information support for patients about anticipated adverse effects and management of those adverse effects may
increase persistence.98
Financial constraints are another reported cause of nonpersistence with adjuvant endocrine therapy. One study of patients
taking tamoxifen noted that 60% of patients who discontinued
therapy early reported this issue as a key factor.103 It is likely that
the out-of-pocket costs of AIs (Table 6) pose an even greater
barrier to patients with little or no prescription coverage or who are
Table 6. Cost of Therapies
Cost ($)
Drug
Per Unit
30-Day
Supply
Anastrozole (Arimidex), 1 mg
Exemestane (Aromasin), 25 mg
Letrozole (Femara), 2.5 mg
Tamoxifen (Nolvadex), 20 mg
Tamoxifen, 20 mg
12.66
11.38
13.91
3.67
0.73
379.80
341.40
417.30
110.10
21.90
NOTE. US dollars; www.drugstore.com.
subject to cost-sharing strategies (ie, co-payments). Although physicians are generally reluctant to discuss costs of cancer therapies,109 inquiring about patients’ cost concerns may help direct
patients to assistance programs and create opportunities to stress
the benefits of persistence with adjuvant endocrine therapy. ASCO
supports the development of resources to facilitate patientprovider communication about costs of cancer care.110
In summary, optimal adjuvant endocrine therapy includes careful consideration of tumor risk, treatment benefit, treatment adverse
effects, and patient adherence. Clinicians should discuss realistic,
quantitative risks of cancer recurrence and death and benefits from
cancer therapy as part of the adjuvant decision-making process. Clinicians should alert patients to common adverse effects of therapy and
serially inquire about treatment-related toxicities, patient adherence
to therapy, and factors that may affect adherence and persistence.
HEALTH DISPARITIES
ASCO clinical practice guidelines represent expert recommendations
derived from high-quality evidence on the best practices in disease
management. However, racial, ethnic, and socioeconomic disparities
in quality of health care exist and persist in the United States. Members
of racial and ethnic minority groups and patients with fewer financial
resources tend to have a higher burden of comorbid illness, are more
likely to be uninsured or underinsured, face more challenges in accessing care, and are at greater risk of receiving poor-quality care than
other Americans.111-115
Representation of minorities in clinical trials of adjuvant endocrine therapy is low. To date, no evidence indicates differences in
therapeutic benefit between black and white women receiving adjuvant tamoxifen in the clinical trials setting. A few studies suggest that
women who belong to minority groups are less likely to receive
guideline-concordant endocrine therapy. One study examined prescribing patterns, considering 677 patients diagnosed with breast
cancer in 1999 to 2000 who were treated at six hospitals in New
York City. Findings indicated that rates of guideline-concordant
adjuvant endocrine therapy prescribing were lower in Hispanic
(71%) and black (75%) patients compared with non-Hispanic
white (85%) patients.116
Only small samples of minority patients were included in
persistence studies, largely preventing an examination of correlates
and mechanisms of optimal therapy in minorities. Hispanics have
largely been omitted. In one study, nonwhite patients (who were
pooled because they represented only 17% of the sample) were
more likely to stop adjuvant endocrine therapy before completing
the planned treatment course (adjusted odds ratio, 1.5; 95% CI, 1.1
to 1.9).102 Other studies that addressed racial differences in adherence to or persistence with endocrine therapy generated mixed
results.103,108 Race was not associated with adherence or persistence in one recently published claims-based study of low-income
patients (884 white and 607 black) with Medicaid; 80% of patients
who started adjuvant endocrine therapy were persistent with medication at 1 year of follow-up.117 Awareness of disparities in quality
of care should be considered in the context of this clinical practice guideline.
© 2010 by American Society of Clinical Oncology
11
Burstein et al
SUMMARY AND FUTURE DIRECTIONS
Incorporation of an AI improves disease-free survival in postmenopausal women with hormone receptor–positive breast cancer compared with tamoxifen alone. Thus, the Update Committee
recommends AI therapy at some point during adjuvant treatment,
either as upfront therapy or as sequential or extended treatment after
tamoxifen. The optimal timing and duration of AI treatment remain
unresolved; it is unclear whether sequential treatment strategies yield
advantages over monotherapy with AIs. The Update Committee recognizes distinct adverse effect profiles of tamoxifen and AIs and believes that consideration of adverse effect profiles and patient
preferences are relevant to deciding whether and when to incorporate
AI therapy for individual patients.
Important and unanswered questions about adjuvant endocrine
therapy in postmenopausal women persist. The Update Committee
identified the following issues as clinically significant for ongoing
research studies and treatment recommendations:
● Long-term follow-up to characterize the lasting clinical effects
of AI therapy and impact on survival, survivorship, and quality of life
● Comparisons of currently available AIs against one another
● Determination of optimal schedules for endocrine therapy,
including duration of treatment, interrupted treatment
schedules, and sequencing
● Late adverse effects, particularly in cardiovascular and bone
health, of AI therapy
● Strategies to improve adherence with recommended adjuvant
treatments and minimize disparities in access to therapy
● Interventions to minimize treatment-related adverse effects,
including menopausal symptoms, osteoporosis, sexual dysfunction, and arthralgias, among women receiving adjuvant
endocrine therapy
● Comparative effectiveness analyses of adjuvant endocrine
strategies based on efficacy, toxicity, and cost
● Development of biomarker(s) for selection of endocrine strategies and for refining estimates of risk in postmenopausal,
ER-positive breast cancer
● Identification of predictors of late (after 5 or 10 years) recurrence to tailor durations of therapy
● Definitive analyses of the role of drug metabolism and pharmacogenetics as predictors of benefit and/or treatment options in adjuvant endocrine therapy
● Incorporation of novel antiestrogens or other treatments to
enhance endocrine therapy and reduce risk of recurrence
● Clarification of the relevance of AI therapy and ovarian suppression among women who are premenopausal at the time of
breast cancer diagnosis
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12
© 2010 by American Society of Clinical Oncology
The Update Committee anticipates that the results from prospective randomized trials, ongoing correlative science studies, longterm follow-up from major adjuvant studies, and smaller, focused
investigations of related scientific and clinical questions regarding
endocrine treatment will continue to inform and revise the recommendations for adjuvant endocrine therapy in the years ahead.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Jennifer Malin, Pfizer (C); Eleftherios P. Mamounas, Novartis (C),
Pfizer (C) Stock Ownership: None Honoraria: Karen E. Gelmon,
Novartis, Astra Zeneca, Pfizer; Eleftherios P. Mamounas, Pfizer,
Novartis; Vered Stearns, AstraZeneca Research Funding: Vered Stearns,
Novartis, Pfizer Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Harold J. Burstein, Jennifer J. Griggs
Administrative support: Ann Alexis Prestrud, Jerome Seidenfeld,
Mark R. Somerfield
Collection and assembly of data: Harold J. Burstein, Ann Alexis
Prestrud, Jerome Seidenfeld, Jennifer J. Griggs
Data analysis and interpretation: Harold J. Burstein, Ann Alexis
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Alexander J. Solky, MaryFran R. Sowers, Vered Stearns, Eric P. Winer,
Mark R. Somerfield, Jennifer J. Griggs
Manuscript writing: Harold J. Burstein, Ann Alexis Prestrud, Jerome
Seidenfeld, Holly Anderson, Thomas A. Buchholz, Nancy E. Davidson,
Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis, Jennifer
Malin, Eleftherios P. Mamounas, Diana Rowden, Alexander J. Solky,
MaryFran R. Sowers, Vered Stearns, Eric P. Winer, Mark R. Somerfield,
Jennifer J. Griggs
Final approval of manuscript: Harold J. Burstein, Ann Alexis Prestrud,
Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz, Nancy E.
Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis,
Jennifer Malin, Eleftherios P. Mamounas, Diana Rowden, Alexander J.
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trial. Ann Oncol 20:1489-1498, 2009
85. Brufsky A, Harker WG, Beck JT, et al:
Zoledronic acid inhibits adjuvant letrozole-induced
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86. Bundred NJ, Campbell ID, Davidson N, et al:
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87. Hillner BE, Ingle JN, Chlebowski RT, et al:
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88. Burstein HJ, Winer EP: Aromatase inhibitors
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90. Henry NL, Giles JT, Ang D, et al: Prospective
characterization of musculoskeletal symptoms in
early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat 111:365372, 2008
91. Sestak I, Sapunar F, Cuzick J: Aromatase
inhibitor-induced carpal tunnel syndrome: Results
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92. Bertelli G, Hall E, Ireland E, et al: Long-term
endometrial effects in postmenopausal women with
early breast cancer participating in the Intergroup
Exemestane Study (IES): A randomised controlled
trial of exemestane versus continued tamoxifen
after 2-3 years tamoxifen. Ann Oncol 21:498-505,
2010
93. Duffy SR, Distler W, Howell A, et al: A lower
incidence of gynecologic adverse events and interventions with anastrozole than with tamoxifen in the
ATAC trial. Am J Obstet Gynecol 200:80.e1-7, 2009
94. Goss PE, Ingle JN, Martino S, et al: Outcomes of women who were premenopausal at
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95. Burstein HJ, Mayer E, Patridge AH, et al:
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96. Smith IE, Dowsett M, Yap YS, et al: Adjuvant
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97. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of
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98. Haynes RB, Ackloo E, Sahota N, et al: Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2: CD000011, 2008
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100. Ravdin PM: A computer program to assist in
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102. Partridge AH, Wang PS, Winer EP, et al:
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108. Kahn KL, Schneider EC, Malin JL, et al:
Patient centered experiences in breast cancer: Predicting long-term adherence to tamoxifen use. Med
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109. Schrag D, Hanger M: Medical oncologists’
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117. Kimmick G, Anderson R, Camacho F, et al:
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118. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
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119. Boccardo F, Rubagotti A, Amoroso D, et al:
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120. Coombes RC, Hall E, Gibson LJ, et al: A
randomized trial of exemestane after two to three
years of tamoxifen therapy in postmenopausal
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350:1081-1092, 2004
121. Jakesz R, Jonat W, Gnant M, et al: Switching
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122. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women
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■ ■ ■
Acknowledgment
The Update Committee thanks Kaitlin Einhaus; Karen Hagerty; Christina H. Jagielski; Carol Palackdharry; Richard Theriault, DO; Linda
Vahdat, MD; Robert Langdon, MD; and Sandra Swain, MD; the external reviewers for the Journal of Clinical Oncology, and the American
Society of Clinical Oncology Board of Directors and Clinical Practice Guideline Committee for their thoughtful reviews of earlier drafts.
Appendix
Search Strategy for MEDLINE (PUBMED)
(Breast neoplasms[mesh] NOT (“Breast Neoplasms, Male”[Mesh] OR “Phyllodes Tumor”[Mesh] OR “Carcinoma, Ductal, Breast”
[Mesh]) OR (“Breast”[Mesh] AND (“Carcinoma”[Mesh] OR “Adenocarcinoma”[Mesh] OR “Neoplasms”[Mesh]))) OR ((breast[tiab]
OR mammary[tiab]) AND (cancer[tiab] OR cancers[tiab] OR tumor[tiab] OR tumors[tiab] OR tumour[tiab] OR tumours[tiab] OR
malignan*[tiab] OR carcinoma[tiab] OR carcinomas[tiab] OR adenocarcinoma[tiab] OR adenocarcinomas[tiab])) AND
((“Aromatase Inhibitors”[Mesh] OR aromatase inhibitors[nm] OR “aromatase inhibitor”[TIAB] OR “aromatase inhibitors”
[TIAB] OR “aromatase inhibition”[TIAB] OR “anastrozole ”[Substance Name] OR anastrozole [tiab] OR arimedex[tiab] OR “letrozole”
© 2010 by American Society of Clinical Oncology
15
Burstein et al
[Substance Name] OR “letrozole ”[tiab] OR femara[tiab] OR aromasil[tiab]OR exemestane [Substance Name] OR “exemestane”[tiab]
OR aromasin[tiab] OR aromasine[TIAB] OR Tamoxifen[Mesh] OR Tamoxifen[substance name] OR “Tamoxifen”[tiab] OR novaldex
[tiab]) NOT (aminoglutethimide[mesh] OR aminoglutethimide[tiab])) AND
(((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh] OR clinical trial[pt] OR
“clinical trial”[tiab] OR “clinical trials”[tiab] OR clinical trials as topic[mh] OR controlled clinical trials as topic[mh] OR randomized
controlled trials as topic[mh] OR clinical trials, phase II as topic[mh] OR clinical trials, phase III as topic[mh] OR clinical trials, phase IV
as topic[mh] OR clinical trial, phase II[pt] OR clinical trial, phase III[pt] OR clinical trial, phase IV[pt] OR random allocation[mh] OR
“random allocation”[tiab] OR “randomly allocated”[tiab] OR double-blind method[mh] OR single-blind method[mh]) OR ((random[tiab] OR randomly[tiab] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab]) AND (clinical[tiab] OR control[tiab] OR controlled[tiab] or control groups[mh])) OR ((single[tiab] OR single-[tiab] OR double[tiab] OR
double-[tiab] OR triple[tiab] OR triple-[tiab] OR multi[tiab] OR multi-[tiab]OR evaluator[tiab] OR assessor[tiab] OR interviewer[tiab]) AND (mask[tiab] OR masked[tiab] OR masking[tiab] OR blind[tiab] OR blinded[tiab] OR blinding[tiab])) OR ((placebos[mh]
OR placebo[tiab] OR placebos[tiab] OR random[tiab] OR randomly[tiab] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomization[tiab]) AND (research design[mh] OR “comparative study”[tiab] OR comparative study[pt] OR evaluation
studies as topic[mh:noexp] OR evaluation studies[pt] OR “evaluation study”[tiab] OR “evaluation studies”[tiab] OR validation studies
as topic[mh] OR follow-up studies[mh] OR “follow-up study”[tiab] OR “follow up study”[tiab] OR “follow-up studies”[tiab] OR
“follow up studies”[tiab] OR prospective studies[mh] OR prospective[tiab] OR epidemiologic research design[mh] OR epidemiologic
methods[mh] OR epidemiologic study characteristics as topic[mh] OR epidemiologic studies[mh] OR intervention studies[mh] OR
cross-over studies[mh]))) NOT (clinical trial, phase I[pt] OR clinical trials, phase I as topic[mh]) NOT (animals[mh] NOT humans[mh])) AND English[la]
Table A1. Update Committee Members
Member
Affiliation
Harold J. Burstein, MD, PhD, Co-Chair
Jennifer J. Griggs, MD, MPH, Co-Chair
Holly Anderson, RN, BSN, Patient Representative
Diana Rowden, MS, Patient Representative
Thomas A. Buchholz, MD
Nancy E. Davidson, MD
Karen A. Gelmon, MD
Sharon Hermes Giordano, MD
Clifford Hudis, MD
Jennifer Malin, MD, PhD
Eleftherios P. Mamounas, MD
Alexander J. Solky, MD
MaryFran R. Sowers, PhD
Vered Stearns, MD
Eric P. Winer, MD
Dana-Farber Cancer Institute
University of Michigan Comprehensive Cancer Center
Breast Cancer Coalition of Rochester
Susan G. Komen for the Cure
M. D. Anderson Cancer Center
University of Pittsburgh Cancer Institute
British Columbia Cancer Agency
M. D. Anderson Cancer Center
Memorial Sloan-Kettering Cancer Center
Greater Los Angeles Veterans Affairs Healthcare System
Aultman Health Foundation
Interlakes Oncology and Hematology
University of Michigan
Johns Hopkins School of Medicine
Dana-Farber Cancer Institute
16
© 2010 by American Society of Clinical Oncology
ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer
Table A2. Time to Recurrence
Trial
Primary
ATAC21 ITT
Sequential
TEAM57 EXE/TAM v EXE ITT
IES14
N-SAS BC-039
ARNO 9534
Extended
MA.1726
NSABP B-3337
Median
Follow-Up
(months)
Range
(months)
100
61
55.7
42
30.1
64
30
0-89.7
3.2-60
⬍ 12 to ⱖ 84
No. of Patients
Observed
Time to Recurrence Events
AI
AI
Comparator
No.
3,125
3,116
538
4,868
2,352
347
489
4,898
2,372
349
490
265
15
36
2,583
783
2,587
779
136
17
Comparator
%
No.
%
645
10.9
10.2
4.3
7.4
325
27
47
7.7
9.6
5.3
2.2
190
37
7.3
4.7
HR
95% CI
P
⬍ .001
0.81
0.73 to 0.91
0.94
0.7
0.54
0.83 to 1.06
0.58 to 0.83ⴱ
0.29 to 1.02†‡
NR
.293
NR
.06‡
NR
NR
NR§
NR
.004
0.44
NOTE. Percent calculated as number of events divided by number of patients observed.
Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ITT, intent to treat; TEAM, Tamoxifen
Exemestane Adjuvant Multinational (trial); EXE, exemestane; TAM, tamoxifen; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group);
ARNO, Arimidex-Nolvadex (trial); NR, not reported; NSABP, National Surgical Adjuvant Breast and Bowel Project.
ⴱ
Disease recurrence.
†Relapse-free survival.
‡Two different sets of values reported on abstract and poster; table reflects poster (abstract: aromatase inhibitor, N ⫽ 15 关4.3%兴; comparator: N ⫽ 28 关NR兴; hazard
ratio, 0.52; 95% CI, 0.28 to 0.98; P ⫽ .02).
§Relapse-free survival follow-up for all TEAM patients is 33 months (data beyond that point censored).
© 2010 by American Society of Clinical Oncology
17
Burstein et al
Table A3. Disease-Free Survival Subset Analyses
Trial
Primary
ATAC21,65 (Goss PE, et al: J Natl
Cancer Inst 97:1262-1271,
2005) ANA v TAM ITT
Hormone receptor–positive
ANA v TAM ITT
Node-positive
Node-negative
Node-unknown
ER-positive/PR-positive
ER-positive/PR-negative
ER-negative/PR-positive
ER-negative/PR-negative
ER-positive/PR-unknown
ER- and PR-unknown
BIG 1-9842,45,50 LET v TAM
Node-negative or node-unknown
Node-positive
ERBB2-negative
ERBB2-positive
Low Ki-67
High Ki-67
ER-positive/PR-positive
ER-positive/PR-negative
ER-positive/PR-unknown
Sequential
BIG 1-9842 TAM/LET v LET
Node-negative or node-unknown
Node-positive
LET/TAM v LET
Node-negative or node-unknown
Node-positive
IES14 ITT
Node-negative
Node-positive
ER-positive/ER-unknown
ER and PR high
Extended
MA.1726 ITT§
Node-positive
Node-negative
ITT§
ER-positive/PR-positive
ER-positive/PR-negative
ER-negative/PR-positive
NSABP B-3337
Node-positive
Node-negative
ER-positive and PR-positive
ER-positive or PR-positive
Median
Follow-Up Range
(months) (months)
100
100
68
68
68
68
68
68
68
68
68
68
76
71
71
51
51
51
0-126
0-126
Disease-Free Survival Events
No. of Patients
Observed
AI
AI
Comparator No.
3,125
3,116
2,618
2,598
Total: 9,366
NR
NR
NR
Total: 5,719
Total: 1,372
Total: 220
Total: 703
Total: 518
Total: 743
2,463
2,459
1,376
1,404
1,050
1,017
1,648
1,646
134
105
730
703
51
25.8
25.8
25.8
631
2,542
808
579
71
71
71
71
71
71
55.7
55.7
55.7
55.7
191
50
17
66
22
46
509
200
303
178
27
56
26.1
23.6
12.9
NR
NR
NR
10
11
27
28
13
19
20.7
14.5
28.9
1.08
20.1
7.7
621
2,513
823
575
66
179
89
70
1,548
894
635
1,540
920
611
2,352
1,217
1,050
2,296
NR
1,546
886
645
1,546
886
645
2,372
1,230
1,039
2,306
NR
259
100
154
236
101
135
354
NR
NR
339
2,583
1,174
2,587
1,194
164
64
1,295
1,281
30
30
30
30
30
30
30
30
30
2,583
1,907
309
100
783
Total:
Total:
Total:
Total:
2,587
1,902
327
100
779
755
807
1,266
248
0-89.7
0-89.7
0-89.7
0-89.7
NR
64
64
16-95
817
618
402
Comparator
%
92
60
19
4
37
No.
HR
222
102
25
79
20
47
565
227
332
240
32
66
28.5
27.0
16.0
NR
NR
NR
12
24
33
32
11
19
23.0
16.2
32.6
14.6
30.5
9.4
0.90
0.85
0.79
0.84
0.68
0.48
0.84
0.43
0.79
0.90
1.29
0.96
0.88
0.89
0.83
0.72
0.62
0.81
10.5
7
11
12.1
115
208
107
92
18.5
8.3
13
16
0.53
0.84
0.83
0.72
16.7
11.2
24.2
15.3
248
102
145
248
102
145
455
NR
NR
439
16.0
11.5
22.5
16.0
1.05
0.96
1.13
0.96
0.97
0.98
0.76
0.74
0.72
0.75
0.686
14.8
NR
887
702
498
%
19.0
NR
6.3
235
9.1
0.68
91.7 DFS at
87.8 DFS at 0.74
4 years
4 years
97.0 DFS at
94.6 DFS at 0.51
4 years
4 years
3.6
155
6.0
0.58
3.0
117
6.0
0.49
6.0
17
5.0
1.21
4.0
5
5.0
0.56
4.7
52
6.7
0.68
NR
NR
0.5
NR
NR
1.13
NR
NR
0.7
NR
NR
0.52
95% CI
P
0.82 to 0.99
.025
0.76 to 0.94
.003
⬍ .001
0.70 to 0.90ⴱ
0.70 to 1.00
0.55 to 0.84
0.23 to 1.00
NR
.07
0.69 to 1.02ⴱ
⬍ .001
0.31 to 0.61ⴱ
.5
0.43 to 1.47ⴱ
.5
0.65 to 1.25ⴱ
.4
0.71 to 2.37ⴱ
.8
0.64 to 1.44ⴱ
0.78 to 0.99
.03
0.74 to 1.08
NR†
0.71 to 0.98
NR
0.59 to 0.87
NR
0.37 to 1.03
NR
0.57 to 1.15 .09 (for interaction
between low
and high Ki-67)
0.39 to 0.72
0.49 to 1.03
.09†
0.62 to 1.10
.18†
0.53 to 0.98
.04†
0.84 to 1.32‡
0.67 to 1.38
0.84 to 1.52
0.76 to 1.21‡
0.67 to 1.39
0.72 to 1.59
0.66 to 0.88
0.58 to 0.94
0.61 to 0.86
0.65 to 0.87
NR
NR
NR
NR
NR
NR
⬍ .001
NR
NR
⬍ .001
NR
0.55 to 0.83
0.58 to 0.94
⬍ .001
.01
0.35 to 0.75
⬍ .001
0.45 to 0.76
0.36 to 0.67
0.63 to 2.34
0.15 to 2.12
⬍ .001
NR
NR
NR
.07
.01
.74
.15
.17
0.30 to 0.86
NR
NR
NR
NOTE. Percent calculated as number of events divided by number of patients observed.
Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; ITT, intent
to treat; NR, not reported; ER, estrogen receptor; PR, progesterone receptor; BIG, Breast International Group; LET, letrozole; IES, Intergroup Exemestane Study;
DFS, disease-free survival; NSABP, National Surgical Adjuvant Breast and Bowel Project.
ⴱ
Time to recurrence.
†Relapse-free survival, local and distant recurrence, contralateral breast cancer, and death without recurrence.
‡99% CIs used to account for multiple comparisons.
§Seventeen patients omitted from ITT analysis.
18
© 2010 by American Society of Clinical Oncology
ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer
Table A4. Adverse Cardiovascular (cardiovascular deaths, ischemic cardiac disease, hypertension, high cholesterol) Effects
Cardiovascular Events
Trial
Median
Follow-Up
(months)
ATAC (Howell A, et al:
Lancet 365:60-62, 2005;
Arimidex, Tamoxifen,
Alone or in Combination
Trialists’ Group, et al:
Lancet Oncol 7:633-643)
2006
68
BIG 1-9815,36,41
30.1
ABCSG-830
75
ITA10 (Boccardo F, et al:
J Clin Oncol 23:51385147, 2005)
64
TEAM57
61
IES14
55.7
ARNO 9534
30.1
N-SAS BC-039
42
MA.1725
30
Grades
3 to 5
Cardiac
Events
Arm
ANA
TAM
OR
95% CI
P
LET
TAM
RR
P
TAM/ANA
TAM
P
ANA
TAM
P
TAM/EXE
EXE
P
EXE
TAM
P
ANA
TAM
TAM/ANA
TAM
LET
Placebo
P
All Cardiac
Events
No. of
Patients No.
% No.
%
3,092
3,094
Cardiovascular
Deaths
No.
%
49
46
2
1
NR
NR
NR
3,975
3,988
1,469
1,453
223
225
140
127
5.7
5.2
NR
.45
127 6.5
130 6.0
.479
17 7.6†
14
96 2.4
57 1.4
1.68
.001
445
452
347
349
2,572
2,577
No.
%
4.10
3.40
1.23
0.95 to 1.60
.1
54 2.2
45 1.8
NR
.42
Grades
3 to 5
Ischemic
Cardiac
Disease
Any Grade
Hypertension
High
Cholesterol
No.
No.
No.
%
127
104
%
402
349
45 1.1
29 0.7
1.55
.06
13
11
1.18
0.69 to 1.44
.04
150
3.8
135
3.4
1.11
.37
6.2
.6
23 1
18 ⬍ 1
NR
⬍1
⬍1
14
13
185
162
NR
9
4
0.6¶
0.9
5.80
5.60
.76
9
3
2.73
2.02 to 3.69
⬍ .001
43.60ⴱ
19.20
NR
9.3ⴱ
6
60
77
382 16.5§
350 15.0
.16
%
278
108
19
4,814
4,852
2,320
2,338
All
Ischemic
Cardiac
Disease
1.2‡
1.6
.183
8.0
6.9
.17
2.0
0.9
215
293
185 8
162 6.9
.17
4.5
6.0
.001
830
35.8
772
33.0
.05
4.0
.04
134 2.8
227 4.7
⬍ .001
166 7.2
141 6.0
.12
16.00
16.00
.79
Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR, not reported; BIG, Breast
International Group; LET, letrozole; RR, risk ratio; ABCSG, Austrian Breast and Colorectal Cancer Study Group; ITA, Italian Tamoxifen Anastrozole (trial); TEAM,
Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial); N-SAS, National
Surgical Adjuvant Study (Group).
ⴱ
Lipid metabolism disorder.
†Cardiovascular disease.
‡Myocardial ischemia/infarction.
§Excludes venous thromboembolic events.
¶Heart disease.
© 2010 by American Society of Clinical Oncology
19
Burstein et al
Table A5. Adverse Cardiovascular (ischemic cerebrovascular, stroke, or TIA thrombosis) Effects
Cardiovascular Events
Trial
Median
Follow-Up
(months)
ATAC21 (Howell A, et al: Lancet
365:60-62, 2005; Arimidex,
Tamoxifen, Alone or in
Combination Trialists’
Group, et al: Lancet Oncol
7:633-643, 2006)
68
BIG 1-9841
30.1
ABCSG-1223
47.8
ABCSG-830
75
TEAM57
61
IES14
55.7
ARNO 9534
30.1
N-SAS BC-039
42
Arm
ANA
TAM
OR
95% CI
P
LET
TAM
RR
P
ANA ⫹ GOS
TAM ⫹ GOS
TAM/ANA
TAM
P
TAM/EXE
EXE
P
EXE
TAM
P
ANA
TAM
TAM/ANA
TAM
No. of
Patients
3,092
3,094
All Ischemic
Cerebrovascular
Events
Grades 3 to 5
Stroke or TIA
No.
%
No.
%
No.
62
88
2
2.8
20
34
0.16ⴱ
0.28
87
140
0.70
0.50 to 0.97
.03
3,975
3,988
NR
NR
NR
47
49
1.2
1.2
1
0.99
453
451
1,469
1,453
4,814
4,852
35
51
0.7
1.1
.112
2,320
2,338
445
452
347
349
All Venous
Thrombosis
Events
3
1
%
2.80
4.50
0.61
0.46 to 0.80
⬍ .001
68
1.7
154
3.9
0.44
⬍ .001
0
0
44
2.3†
47
2.2
.833
97
2.0
45
0.9
⬍ .001
28
1.2
54
2.3
.004
Grades 3 to 5
Venous
Thrombosis
Events
No.
%
35
92
0.9
2.3
0.38
⬍ .001
7
19
⬍1
⬍1
NR
0.7
0.2
0.3
0.0
Abbreviations: TIA, transient ischemic attack; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR,
not reported; BIG, Breast International Group; LET, letrozole; RR, risk ratio; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; TEAM,
Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial); N-SAS, National
Surgical Adjuvant Study (Group).
ⴱ
Cerebrovascular accidents.
†Embolism, thromboses.
20
© 2010 by American Society of Clinical Oncology
ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer
Table A6. Adverse Musculoskeletal Effects
Musculoskeletal Events
Trial
Median
Follow-Up
(months)
ATAC18,21 (Howell A, et al:
Lancet 365:60-62,
2005; Arimidex,
Tamoxifen, Alone or in
Combination Trialists’
Group, et al: Lancet
Oncol 7:633-643, 2006)
68
BIG 1-9815,36
30.1
ABCSG-1223
47.8
ABCSG-830
75
ITA10
64
TEAM57
61
IES13,14
55.7
N-SAS BC-039
42
ARNO 9534
30.1
ABCSG-6a31
62.3
NSABP B-3337
MA.1725 (Goss PE, et al:
J Natl Cancer Inst 97:
1262-1271, 2005)
30
30
Arm
ANA
TAM
OR
95% CI
P
LET
TAM
P
ANA ⫹ GOS
TAM ⫹ GOS
TAM/ANA
TAM
P
ANA
TAM
P
TAM/EXE
EXE
P
EXE
TAM
P
TAM/ANA
TAM
ANA
TAM
ANA
Placebo
OR
95% CI
P
EXE
Placebo
P
LET
Placebo
P
Bone Pain
No. of
Patients No.
%
3,092
3,094
Musculoskeletal
Pain
No.
%
132
235
4a
8
0.54
0.41 to 0.72
⬍ .001
Arthralgia
No.
%
1,100 35.6
911 29.4
1.32
1.19 to 1.47
⬍ .001
3,975
3,988
451
453
1,469
1,453
128 28.3
94 20.8
223 11.4e
179 8.2
⬍ .001
112 4.7
52 11.5
223
225
22
15
4,814
4,852
302
188
Osteoporosis
No.
%
Fracture
Rate
No.
Decrease
in
Decrease Lumbar
in Hip
Spine
BMD
BMD
%
11b
375 12.1 ⫺7.24c
7
234 7.6
0.74
1.49
1.55
NR
1.18 to 1.88 1.25 to 1.77
NR
⬍ .001
⬍ .001
NR
196 8
132 5.4
⬍ .001
1 0.2
1 0.2
69 3.5
35 1.6
⬍ .001
325
226
⫺6.08c
⫺2.77
NR
NR
NR
⫺7.8%d
⫺4.5%
9.9f
6.7
.2
6.3g
3.9
⬍ .001
488
21.0
376
16.1
⬍ .001
2,320
2,338
347
349
445
452
387
469
86 18.3i
95 24.5
1.55
1.11 to 2.17
.009
799
0.50j
799
0.70
NR
2,572
2,577
5
6
.67
961 20.0
1,140 23.5
⬍ .001
432 18.6
275 11.8
⬍ .001
50.4
31.8
52 11.7h
22 4.9
259
5.4
478
9.9
⬍ .001
169
7.3
128
5.5
.01
13
4
2.9
0.9
1.00j
0.50
25
21
⬍ .001
⫺2.799
⫺1.011
NR
⫺3.726
⫺0.412
NR
10 2.2
10 2.2
28
20
NR
15k
12
.004
170 3.5
249 5.1
⬍ .001
100 4.3
73 3.1
.03
.33
8.10
6
.003
5.30 ⫺3.60%l
4.60 ⫺0.71%
.25
.044
⫺5.35%l
⫺0.70%
.008
Abbreviations: BMD, bone mineral density; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR, not
reported; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian Tamoxifen
Anastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical
Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.
a
Muscle cramps.
b
Osteoporosis or osteopenia.
c
Change in BMD from baseline to year 5.
d
Changes at 60 months.
e
Bone or joint disorder.
f
Includes both musculoskeletal disorders and bone fractures.
g
Muscle cramps/disorders.
h
Both arthralgia and bone pain.
i
Grades 1 to 4 only.
j
Grades 3 and 4 only.
k
Muscle pain.
l
BMD from 24 months: N (LET) ⫽ 122; N (placebo) ⫽ 104 cases only.
© 2010 by American Society of Clinical Oncology
21
Burstein et al
Table A7. Adverse Gynecologic Effects
Gynecologic Events
Trial
Median
Follow-Up
(months)
ATAC (Howell A, et al: Lancet
365:60-62, 2005)
68
BIG 1-986,36
25.8
ABCSG-1223
47.8
ABCSG-830
75
ITA10
64
TEAM57
61
IES6,14
N-SAS BC-039
55.7
42
ARNO 9534
30.1
ABCSG-6a31
62.3
MA.176 (Goss PE, et al:
J Natl Cancer Inst 97:
1262-1271, 2005)
30
Arm
ANA
TAM
OR
95% CI
P
LET
TAM
P
ANA ⫹ GOS
TAM ⫹ GOS
TAM/ANA
TAM
P
ANA
TAM
P
TAM/EXE
EXE
P
EXE
TAM
P
TAM/ANA
TAM
ANA
TAM
ANA
Placbeo
OR
95% CI
P
LET
Placebo
P
No. of
Patients
3,092
3,094
Gynecologic
Disorders
No.
%
3a
10
0.27
0.20 to 0.37
⬍ .001
95
324
3,975
3,988
Vaginal Bleeding
No.
%
167
317
5.4
10.2
0.50
0.41 to 0.61
⬍ .001
3.3
6.6
⬍ .001
Vaginal
Discharge
Endometrial
Biopsy
Endometrial
Cancer
No.
No.
No.
%
%
109
3.5
408 13.2
0.24
0.19 to 0.30
⬍ .001
%
223
225
4,814
4,852
2,320
2,338
347
349
445
452
387
469
2,572
2,577
2.3
9.1
⬍ .001
0.4
0.1
.040
5
0.2
11
0.5
NR
0
0.3
0
2
0.4
145
196
4
11
6.0
8.0
.005
%
1
5
0.2
1.1
0.2
0.8
0.29
0.11 to 0.80
.02
6
0.1
15
0.3
NR
5.0
402
8.4 187
3.9d
2.3
123
2.5
20
0.4
⬍ .001
⬍ .001
⬍ .001
91
4.6
65
2.8
1 ⬍ 0.1e
131
6.5
91
3.9
20
0.9
.008
.04
⬍ .001
9.2g
16.1
8.0
24.4
7
1.6
8
1.8e
9
2.0
39
8.6
3
0.8h
23 59
1
0.2
13
2.8
3.84
2.34
1.40 to 37.06 1.17 to 4.68
.245
.017
243
114
No.
5
17
453
451
442
22.6
681
31.2
⬍ .001
16
7.2b
9
4.0
.1
94
2.0c
64
1.3
.017
Uterine
Polyps
17
7
24
1.2f
65 (3.2)
⬍ .001
4
15
0.9
3.3
.12
Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; BIG, Breast International Group; LET,
letrozole; NR, not reported; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian Tamoxifen Anastrozole (trial); TEAM, Tamoxifen
Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group); ARNO,
Arimidex-Nolvadex (trial).
a
Gynecologic events.
b
Gynecologic symptoms.
c
Other vulvovaginal disorders.
d
Endometrial abnormalities.
e
Endometrial hyperplasia.
f
Uterine fibroids or polyps.
g
Genital bleeding.
h
Grades 1 and 2 only.
22
© 2010 by American Society of Clinical Oncology
ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer
Table A8. Adverse Climacteric Effects
Climacteric Symptoms
Trial
Median
Follow-Up
(months)
ATAC (Howell A, et al:
Lancet 365:60-62,
2005; Arimidex,
Tamoxifen, Alone
or in Combination
Trialists’ Group, et
al: Lancet Oncol
7:633-643, 2006)
68
BIG 1-9836
25.8
ABCSG- 1223
47.8
ABCSG-830
75
ITA10
64
TEAM57
61
IES14,19
55.7
N-SAS BC-039
42
ARNO 9534
30.1
ABCSG-6a31
62.3
NSABP B-3337
30
MA.17 (Goss PE, et
al: J Natl Cancer
Inst 97:12621271, 2005)
30
Arm
No. of
Patients
ANA
TAM
OR
95% CI
P
LET
TAM
P
ANA ⫹ GOS
TAM ⫹ GOS
ANA/TAM
TAM
P
ANA
TAM
P
TAM/EXE
EXE
P
EXE
TAM
P
TAM/ANA
TAM
ANA
TAM
ANA
Placebo
OR
95% CI
P
EXE
Placebo
P
3,092
3,094
LET
Placebo
P
2,572
2,577
3,975
3,988
453
451
1,469
1,453
Hot Flashes
No.
%
2,320
2,338
347
349
445
452
387
469
799
799
No.
%
Mood
Disturbance
Decreased
Libido
Nausea
and
Vomiting
Headache
Cognitive
GI
Disorder Symptoms
No.
No.
No.
No.
No.
%
1,104 35.7 575 18.6 597 19.3
1,264 40.9 544 17.6 554 17.9
0.80
1.07
1.10
0.73 to 0.89 0.94 to 1.22 0.97 to 1.25
⬍ .001
.3
.2
33.5
38
⬍ .001
25 5.5
93 20.5
97 21.4b
28 6.2
70 15.5
70 15.5
223
225
4,814
4,852
Fatigue/
Asthenia
4
0
%
%
999 39
998 39
.95
%
32
23
7.1
5.1
%
265
216
63 13.9
59 13.1
50.6 225 9.7 416 17.9
56.9 248 10.6 363 15.5
.30
.03
18.2
16.0
32 8.3
11 2.3
3.97
1.97 to 7.9
⬍ .001
No.
9a
7
1.25
0.98 to 1.60
.02
39
1
393 12.7
12 ⬍ 1
384 12.4
3.28
1.03
1.4 to 7.7 0.88 to 1.19
⬍ .001
.7
1.8
.045
2,127 44.2
1,812 37.3
⬍ .001
957 41.3 526 22.7 228 9.8e
903 38.6 522 22.3 205 8.8
.07
.78
.21
36.3
26.5
20.5f
44.7
25.5
18.1
29 6.5
29 6.4
151 39.0g 41 10.6h
105 22.4
20 4.3
2.44
2.82
1.80 to 3.31 1.62 to 4.90
⬍ .001
⬍ .001
0.90i
0.50
NR
1,486 58
1,383 54
.003
%
3
0.7
0
80 4.1c
51 2.3
.001
67
82
3.4
3.8
.616
26 11.7d
15 6.6
.07
97 4.2a
51 2.2
⬍ .001
4.1a
2.6
1.73
0.81 to 3.70
.159
16
12
272
16j
249
15
NR
Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; BIG, Breast International Group; LET,
letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian Tamoxifen Anastrozole (trial); TEAM, Tamoxifen Exemestane
Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group); ARNO, Arimidex-Nolvadex
(trial); NSABP, National Surgical Adjuvant Breast and Bowel Project; NR, not reported.
a
Diarrhea.
b
Depression or sleep disturbance.
c
Neurologic or psychiatric disorder.
d
GI complaints.
e
Depression.
f
Mood fluctuations.
g
Grade 1 only.
h
Grades 1 to 4.
i
Grade 3 or 4 toxicity.
j
Subset analysis: N (LET) ⫽ 1,813; N (placebo) ⫽ 1,799.
© 2010 by American Society of Clinical Oncology
23
Burstein et al
Potentially relevant publications
identified by electronic searching
and screened for retrieval
(n = 484)
Excluded
(n = 432)
Articles retrieved in full copy
for detailed evaluation
(n = 52)
Excluded
(n = 3)
Articles that met selection
criteria for data extraction
(n = 49)
Other articles recommended by panel
members or identified by hand-searching
(n = 13)
Articles that met selection
criteria for data extraction
(n = 13)
Excluded
(n = 0)
Articles included for
data extraction
(n = 62)
Fig A1. Quorum diagram. Inclusion and exclusion of publications identified for this systematic review.
24
© 2010 by American Society of Clinical Oncology